Carbamic acid derivatives and method for preparing the same

ABSTRACT

Anti-dementia medicaments comprising a carbamic acid derivative or their pharmaceutically acceptable acid addition salts having an anti-amnesic activity as an active ingredient are provided. The carbamic acid derivatives are represented by a general formula (1) ##STR1## wherein Ar denotes an aromatic heterocyclic ring which may have at least one substituent or its benzene-condensed ring, or phenyl group which may have at least one substituent, R 1  denotes hydrogen atom or lower alkyl group, R 2  denotes lower alkyl group which may be substituted with halogen atom, phenyl group which may have at least one substituent, naphthyl group, or five- or six-membered heterocyclic ring and its benzene-condensed ring, X and Y, which may be the same or different, denote sulfur atom or oxygen atom.

BACKGROUND OF THE INVENTION

The present invention concerns carbamic acid derivatives or theirphamaceutically acceptable acid addition salts having anti-amnesicactivity, methods for preparing them, intermediates for preparing them,and anti-dementia comprising the carbamic acid derivatives or theirpharmaceutically acceptable acid addition salts as an active ingredient.

Recently, with elongation of average life, dementia diseases such asAlzheimer type senile dementia have arisen as a great problem in medicalas well as social field.

Patients of dementia show symptom such as loss of intellectual ability,disturbance of memory, disturbance of abstract thinking, verbal aphasia,apraxia, disorientation and so on, and the disturbance of fundamentalfunctions lies in that of formation of memory or expressing ability ofhold memory.

However, up to now there have been hardly any medicament to cure iteffectively and hence rapid development of remedy thereof has beenlonged.

Then, for compounds analogous to carbamic acid derivatives of thepresent invention, there have been known compounds of a general formula(10) ##STR2## wherein R⁵ denotes ethyl, propyl or butyl group and R⁶denotes hydroxy, butoxy, pentoxy, hexyloxy or heptoxy group, which isdescribed in Pharmazie, 44,25, (1989), those of general formulae (11)and (12) ##STR3## wherein R⁷ denotes methyl, ethyl, n-propyl, iso-propylor t-butyl group and R⁸ denotes methyl group or chlorine atom, ##STR4##wherein R⁹ denotes methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butylgroup, R¹⁰ denotes hydrogen atom or methyl group, and R¹¹ denotes methylgroup substituted at o-position, halogen atom substituted at eachposition of o-, m- or p-position, methoxy group substituted atp-position and acetyl group substituted at p-position, having localanesthesia function described in J. Med. Chem., 14, 710 (1971), those ofa general formula (13) ##STR5## wherein R¹² denotes a hydrogen atom,methyl group or chlorine atom and R¹³ denotes a chlorine atom or methylgroup substituted at o-, m- or p-position, synthesized for a comparativecompound in application research of agent of anti-arterial sclerosisdescribed in J. Pharma. Sci., 59, 303 (1970), those of general formula(14) ##STR6## wherein R¹⁴ denotes methyl, ethyl, n-propyl, n-butyl orphenyl group, having inhibitory action against cholinesterase describedin Egypt. J. Pharma. Sci., 26, 267 (1985), and so forth. However, it isunknown at all that these carbamic acid derivatives display anti-amnesiaaction, and further these are different from carbamic acid derivativesof the present invention in the structure thereof.

The object of the present invention lies in providing a medicament forimproving disturbance of memory which is effective to symptoms ofdementia and having high safety factor, in considering the presentstatus of patients of dementia as mentioned above.

SUMMARY OF THE INVENTION

As the result of diligent study for aiming at development of novelanti-dementia medicaments, the inventors of the present invention havefound that carbamic acid derivatives of the present invention and acidaddition salts thereof have an excellent anti-amnesic action. That is,the inventors of the present invention have found that carbamic acidderivatives represented by a general formula (1) ##STR7## wherein Ardenotes an aromatic heterocyclic ring or its benzene-condensed ringwhich may have at least one substituent or phenyl group which may haveat least one substituent, R¹ denotes hydrogen atom or lower alkyl group,R² denotes lower alkyl group which may be substituted with halogen atom,phenyl group which may have at least one substituent, naphthyl group, orfive- or six-membered heterocyclic ring or its benzene-condensed ring,and X and Y, being same or different, denote sulfur atom or oxygen atomor their acid addition salts have a surprisingly excellent anti-amnesiaactivity, and have come to complete the present invention.

In the general formula (1) of the present invention, for the aromaticheterocyclic ring or its benzene-condensed ring which may have at leastone substituent, a group including 1-3 hetero-atom such as for examplepyridyl, pyrimidyl, pyridazyl, pyrazyl, quinolyl and benzothiazolyl canbe exemplified, and for the lower alkyl group, a straight or branchedchain having 1-6 carbon number such as methyl, ethyl, n-propyl andiso-propyl can be exemplified.

For the substituent in the aromatic heterocyclic ring or itsbenzene-condensed ring which may have at least one substituent and inthe phenyl group which may have at least one substituent, naphthylgroup, or five- or six-membered heterocyclic ring or itsbenzene-condensed ring, a halogen atom, lower alkyl group which may besubstituted with halogen atom, lower alkoxy group, cyano group, nitrogroup, amino group wherein this amino group may be substituted with acylgroup, for example acetyl group etc., or may be substituted with 1-2lower alkyl group, hydroxyl group wherein this hydroxyl group may besubstituted with acyl group, for exmaple acetyl group etc., loweralkylthio group, lower alkoxycarbonyl, benzene ring and so on can beexemplified.

For the halogen atom, fluorine, chlorine, bromine and iodine atom can beexemplified, for the lower alkoxy group, a straight or branched chain of1-4 carbon number such as methoxy, ethoxy or propoxy group, and for thelower alkoxycarbonyl group, a group of 1-4 carbon number such asmethoxycarbonyl or ethoxycarbonyl can be exemplified.

The five- or six-membered heterocyclic ring and its benzene-condensedring stands for a saturated or unsaturated monocyclic group and itsbenzene-condensed ring which can be exemplified by, for example,piperidyl, piperazyl, morphoryl, furanyl, thienyl, pyrrolidyl,pirazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl,pyridazyl, pyrazyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl,quinoxalyl, cinnolyl and so on.

The acid addition salts stand for a pharmaceutically acceptable saltsuch as, for example, hydrochloric acid, citric acid, succinic acid,fumaric acid or maleic acid.

For a protecting group of the amino group, for example, a lower acylgroup such as acetyl or propionyl group, an alkoxycarbonyl group such asmethoxy carbonyl or t-butoxy carbonyl group can be exemplified.

For an eliminating group, for example, a halogen atom such as fluorine,chlorine, bromine or iodine, sulfonyloxy group such asp-toluenesulfonyloxy group or methanesulfonyloxy group.

For a condensing agent, for example, carbonyldiimidazoles such asN,N'-carbonyldiimidazole (CDI), N,N'-succinimidyl carbonate (DSC) orN,N'-thiocarbonyldiimidazole (TCDI), phosgene or its analogue such as,for example, trichloromethylchloroformate or triphosgene can beexemplified.

The compound of the present invention can be prepared by the followingpreparative methods.

A compound represented by the general formula (1) can be synthesizedthrough the two processes below with employment of a compoundrepresented by a general formula (2) ##STR8## wherein Ar and X are asmentioned above.

(A) It can be synthesized by allowing a compound represented by thegeneral formula (2) and a corresponding amino compound to react in asuitable solvent such as, for exmaple, methylene chloride, chloroform ortetrahydrofuran at a temperature of -20° C. - room temperature in thepresence of a condensing agent for 2-4 hours.

Herein, the condensing agent means allowing phosgene or its analogue(for example trichloromethylchloroformate, triphosgene and so on) toreact in the presence of a suitable base, for example, triethylamineetc., or introducing carbonyl group of urethane moiety with employingN,N'-carbonyldiimidazole (CDI), N,N'-succinimidyl carbonate (DSC) orN,N'-thiocarbonyldiimidazole (TCDI).

(B) It can be synthesized by allowing a compound represented by thegeneral formula (2) to react with a corresponding isocyanic acid esteror isothiocyanic acid ester in a suitable solvent, for example, ether,benzene, tetrahydrofuran, dichloromethane, dimethylformamide etc. orwithout solvent at a reaction temperature of room temperature - 80° C.,if desired, in the presence of a suitable base such as, for example,sodium hydride or triethylamine, for 1-3 hours.

Herein, the corresponding isocyanic acid ester or isothiocyanic acidester includes also isocyanic acid ester or isothiocyanic acid estersynthesized in situ through Curtius rearrangement after allowing acorresponding carboxylic acid or thiocarboxylic acid to react withthionyl chloride, sodium azide successively, or with diphenylphosphoryeazide (DPPA).

A part of the compounds represented by the general formula (2) ispublicly known and can be synthesized according to Japanese Laid-openPublication No. Hei 2-83369 or Heterocycles, 16(11), 1883 (1981).

The compound represented by the general formula (1) can be alsosynthesized by allowing a compound of a general formula (5) to reactwith a compound of a general formula (6) in a suitable solvent, forexample ethanol, isoamyl alcohol, tertbutanol etc., in the presence of asuitable base, for example sodium hydrogen carbonate, potassiumcarbonate and so on at a temperature of room temperature - boiling pointof the solvent for 5-20 hours.

At this time, the reaction can be enhanced by further adding sodiumacetate, potassium iodide or sodium iodide. ##STR9## wherein Ar, R¹, R²,X and Y are as mentioned before and Z denotes an eliminating group.

Herein, the compound represented by the general formula (5) can besynthesized according to the following scheme. ##STR10## wherein Rdenotes a protecting group of amino group, and R¹, R², X and Y are asmentioned before. That is, the compound represented by the generalformula (5) can be synthesized by converting a compound represented bythe general formula (7) corresponding to a compound of hydroxy- ormercapto-piperidine, nitrogen atom of which is protected, into acompound of the general formula (8) according to the beforementionedmethod of (A) or (B), followed by eliminating the protecting group.

Herein, the reaction of eliminating the protecting group can beconducted by effecting the reaction in a suitable solvent, for exampleethanol, tetrahydrofuran, dimethylformamide and so on in the presence ofacid such as, for example, hydrochloric acid or sulfuric acid at atemperature of room temperature - boiling temperature of the solvent for1-10 hours.

Furthermore, the compounds of the general formula (1), (2), (5), (7),(8) and (9) may have asymmetric carbon depending on the position ofsubstituent on piperidine ring and so there are two kinds of opticalisomer basing on said asymmetric carbon, but each of them or theirmixture are all involved in the scope of the invention.

Further, if pharmaceutically acceptable acid addition salts of thecompound represented by the general formula (1) are required, those ofthe synthesized carbamic acid ester can be obtained by, for example, thereaction with inorganic acid such as hydrochloric acid or with organicacid such as succinic acid.

EXAMPLE

Then, examples of the present invention including preparative examplesthereof are described as follows to explain the present inventionfurther in more details.

Example 1 [4-(1-(4-pyridyl)piperidyl)] 1-naphthylcarbamate

Into a suspension of sodium hydride (320 mg) in N,N-dimethylformamide(30 ml) was dropwise added a solution of 1-(4-pyridyl)-4-piperidinol(1.2 g) in N,N-dimethylformamide at 0° C. under argon atmosphere and themixture was further stirred for 30 minutes. A solution of1-naphthylisocyanate (1.14 g) in N,N-dimethylformamide (10 ml) was addedthereto and the mixture was stirred at room temperature for about 5hours and 30 minutes. After the stirring, the reaction mixture waspoured into water, extracted with methylene chloride, dried overanhydrous magnesium sulfate and then the solvent was distilled off underthe reduced pressure to give crude crystal. This was recrystallized(acetonitrile-N,N-dimethylformamide) to give the title compound 550 mgof pale yellow powder crystal.

Melting point 233°-234° C.

Elementary analysis for C₂₁ H₂₁ N₃ O₂ :

Calculated value C: 72.60, H: 6.09, N: 12.10.

Observed value C: 72.57, H: 6.07, N: 12.20.

Example 2 [4-(1-4-pyridyl)piperidyl)] 4-chlorophenylcarbamate

In a solvent of benzene, 1-(4-pyridyl)-4-piperidinol (400 mg) was heatedand refluxed with 4-chlorobenzoic acid (350 mg), DPPA (0.48 ml) andtriethylamine (0.31 ml) for about 6 hours.

After cooled, the mixture was distilled off under the reduced pressureto give colorless residue. This was recrystallized (acetonitrile) togive 280 mg of the title compound of colorless needle crystal.

Melting point 240°-241° C.

Elementary analysis for C₁₇ H₁₈ ClN₃ O₂ :

Calculated value C: 61.54, H: 5.47, N: 12.66.

Observed value C: 61.57, H: 5.44, N: 12.59.

Example 2A [4-(1-(4-pyridyl)piperidyl)] 4-chlorophenylcarbamate

Into a solution of 4-piperidyl 4-chlorophenylcarbamate (10.11 g) inisoamyl alcohol (200 ml) were added 4-chloropyridine hydrochloride (5.95g) and sodium hydrogen carbonate (6.67 g) successively at roomtemperature, and the mixture was refluxed with heating under argonatmosphere for about 8 hours. After cooled, the mixture was filtered andthe residue was washed with warm ethanol. The filtrate was concentratedand extracted with methylene chloride in a condition of alkali. Thisorganic layer was dried over anhydrous sodium sulfate and the solventwas distilled off under reduced pressure. The obtained residue wascrystallized with addition of ethyl acetate, which was thenrecrystallized to give 3.8 g of the title compound. The instrumentalanalysis data of this compound were identical with those of Example 2.

Example 2B [4-(1-(4-pyridyl)piperidyl)] 4-chlorophenylcarbamatehydrochloride

Into a mixture (40 ml) of ethyleneglycol and DMF was dissolved[4-(1-(4-pyridyl) piperidyl)] 4-chlorophenylcarbamate (500 mg), and themixture was cooled at 0° C. and was introduced with hydrogen chloridegas for 30 minutes. Then, this was distilled off under reduced pressureand precipitated crystal was recrystallized from ethanol to give 250 mgof the title compound.

Melting point 268°-270° C.

Elementary analysis for C₁₇ H₁₈ ClN₃ O₂ ·HCl:

Calculated value C: 55.45, H: 5.20, N: 11.41.

Observed value C: 55.31, H: 5.15, N: 11.28.

Example 3 [4-(1-(4-pyridyl)piperidyl)] N-methyl-4-chlorophenylcarbamate

Into a solution of N-methyl-4-chloroaniline (1.02 ml) in methylenechloride (20 ml) was dropwise added trichloromethylchloroformate (0.66ml) at 0° C. under argon atmosphere. After the mixture was stirred at 0°C. for 1.5 hours, the mixture was added with triethylamine (1.17 ml) andthen stirred at 0° C. for 1 hour. Afterwards, the mixture was dropwiseadded with a solution of 1-(4-pyridyl)-4-piperidinol (1.5 g) inmethylene chloride (15 ml), further added with triethylamine (1.17 ml),and react at 0° C. for 20 minutes, at room temperature for 1 hour afterreturning to room temperature and further by refluxing with heating for2 hours. The reaction mixture was poured into water and extracted withmethylene chloride. This organic layer was dried over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theobtained residue was purified through column chromatography (alumina,ethyl acetate: n-hexane=5:3). The obtained crude crystal was washed withpetroleum ether to give 1.27 g of the title compound of colorless powdercrystal.

Melting point 76°-79° C.

Elementary analysis for C₁₈ H₂₀ ClN₃ O₂ ·2/5H₂ O:

Calculated value C: 61.24, H: 5.94, N: 11.90.

Observed value C: 61.28, H: 5.86, N: 12.05.

Example 4 [4-(1-(4-pyridyl)piperidyl)] phenylcarbamate

Into a solution of 4-piperidylphenylcarbamate (2 g) in isoamyl alcohol(50 ml) were added 4-chloropyridine hydrochloride

(1.4 g), sodium iodide (1.4 g) and sodium hydrogen carbonate (1.6 g)successively at room temperature, and the mixture was refluxed withheating under argon atmosphere for about 12 hours. After cooled, themixture was added with water to terminate the reaction and extractedwith methylene chloride in condition of alkali. This organic layer wasdried over anhydrous sodium sulfate, the solvent was distilled off underreduced pressure and the obtained residue was purified through columnchromatography (alumina, ethyl acetate). The obtained crude crystal was.recrystallized from a mixture of ethyl acetate and ethanol to give 850mg of the title compound of Dale yellow powder crystal.

Melting point 215°-216° C.

Elementary analysis for C₁₇ H₁₉ N₂ O₂ :

Calculated value C: 68.67, H: 6.44, N: 14.13.

Observed value C: 68.40, H: 6.42, N: 14.16.

Example 5-56

According to the same method as in Example 1-4, the following compoundswere obtained.

    __________________________________________________________________________                                                    ANAL.                                                                         [Calcd. (%)/Found (%)]        Example                                                                            Ar           R.sup.1                                                                         R.sup.2     X Y M.P. (Solv.)                                                                              or Mass                       __________________________________________________________________________                                                    (m/e)                          ##STR11##                                                                     5                                                                                  ##STR12##   H                                                                                ##STR13##  O O 136˜137° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.17 H.sub.18                                                             ClN.sub.3 O.sub.2  C:                                                         61.54 H: 5.47 N: 12.66 C:                                                     61.71 H: 5.47 N: 12.37         6                                                                                  ##STR14##   H                                                                                ##STR15##  O O 234˜235° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.17 H.sub.18                                                             FN.sub.3 O.sub.2  C:                                                          64.75 H: 5.75 N: 13.33 C:                                                     64.93 H: 5.73 N: 13.28         7                                                                                  ##STR16##   H                                                                                ##STR17##  O O 230˜231° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.17 H.sub.18                                                             BrN.sub.3 O.sub.2  C:                                                         54.27 H: 4.82 N: 11.17 C:                                                     54.28 H: 4.70 N: 11.09         8                                                                                  ##STR18##   H                                                                                ##STR19##  O O 155˜156° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.17 H.sub.18                                                             ClN.sub.3 O.sub.2  C:                                                         61.54 H: 5.47 N: 12.66 C:                                                     61.43 H: 5.47 N: 12.62         9                                                                                  ##STR20##   H                                                                                ##STR21##  O O Oil         m/e = 332 (M.sup.+  + 1),                                                     205, 78                       10                                                                                  ##STR22##   H                                                                                ##STR23##  O O 147˜148° C. (n-C.sub.6                                           H.sub.14 :AcOEt:EtOH)                                                                     C.sub.21 H.sub.21 N.sub.3                                                     O.sub.2  C: 72.60 H: 6.09                                                     N: 12.10 C: 72.42 H: 6.19                                                     N: 11.99                      11                                                                                  ##STR24##   H                                                                                ##STR25##  O O 123˜124° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.16 H.sub.17                                                             ClN.sub.4 O.sub.2  C:                                                         57.75 H: 5.15 N: 16.84 C:                                                     57.68 H: 5.15 N: 16.72        12                                                                                  ##STR26##   H                                                                                ##STR27##  O O  99˜100° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.16 H.sub.17                                                             ClN.sub.4 O.sub.2  C:                                                         57.75 H: 5.15 N: 16.84 C:                                                     57.70 H: 5.15 N: 16.57        13                                                                                  ##STR28##   H                                                                                ##STR29##  O O 192˜193° C. (n-C.sub.6                                           H.sub.14 :AcOEt:EtOH)                                                                     C.sub.20 H.sub.20 N.sub.4                                                     O.sub.2  C: 68.95 H: 5.79                                                     N: 16.08 C: 68.65 H: 5.73                                                     N: 15.85                      14                                                                                  ##STR30##   H                                                                                ##STR31##  O O 158˜159° C. (n-C.sub.6                                           H.sub.14 :AcOEt:EtOH)                                                                     C.sub.16 H.sub.17                                                             ClN.sub.4 O.sub.2  C:                                                         57.75 H: 5.15 N: 16.84 C:                                                     57.62 H: 5.17 N: 16.74        15                                                                                  ##STR32##   H                                                                                ##STR33##  O O 112˜113° C. (n-C.sub.6                                           H.sub.14 :AcOEt)                                                                          C.sub.16 H.sub.17                                                             ClN.sub.4 O.sub.2  C:                                                         57.75 H: 5.15 N: 16.84 C:                                                     57.79 H: 5.07 N: 16.79        16                                                                                  ##STR34##   H                                                                                ##STR35##  O O 148° C. (n-C.sub.6 H.sub.14                                            :AcOEt:EtOH)                                                                              C.sub.20 H.sub.20 N.sub.4                                                     O.sub.2  C: 68.95 H: 5.79                                                     N: 16.08 C: 68.64 H: 5.78                                                     N: 15.73                      17                                                                                  ##STR36##   H                                                                                ##STR37##  O O 187˜188° C. (n-C.sub.6                                           H.sub.14 :EtOH)                                                                           C.sub.16 H.sub.16                                                             Cl.sub.2 N.sub.4 O.sub.2                                                      : 52.33 H: 4.39 N: 15.26                                                      C: 52.30 H: 4.34 N:                                                           15.19                         18                                                                                  ##STR38##   H                                                                                ##STR39##  O O 199˜200° C. (MeCN:DMF)                                                       C.sub.21 H.sub.19                                                             Cl.sub.2 N.sub.3 O.sub.2                                                      : 60.59 H: 4.60 N: 10.09                                                      C: 60.59 H: 4.54 N:                                                           10.18                         19                                                                                  ##STR40##   H                                                                                ##STR41##  O O 200˜201° C. (MeCN:DMF)                                                       C.sub.25 H.sub.22                                                             ClN.sub.3 O.sub.2  C:                                                         69.52 H: 5.13 N: 9.73 C:                                                      69.44 H: 5.05 N: 9.84         20                                                                                  ##STR42##   H                                                                                ##STR43##  O O 248˜250° C. (EtOH                                                            C.sub.17 H.sub.17                                                             Cl.sub.2 N.sub.3 O.sub.2                                                      : 55.75 H: 4.68 N: 11.47                                                      C: 55.66 H: 4.50 N:                                                           11.45                         21                                                                                  ##STR44##   H                                                                                ##STR45##  O O 136˜138° C. (C.sub.6                                             H.sub.6 :n-C.sub.6 H.sub.14)                                                              C.sub.18 H.sub.18 F.sub.3                                                     N.sub.3 O.sub.2  C: 59.17                                                     H: 4.97 N: 11.50 C: 59.46                                                     H: 4.90 N: 11.52              22                                                                                  ##STR46##   H                                                                                ##STR47##  O O 198˜200° C. (MeCN)                                                           C.sub.18 H.sub.18 F.sub.3                                                     N.sub.3 O.sub.2  C: 59.17                                                     H: 4.97 N: 11.50 C: 59.14                                                     H: 4.91 N: 11.57              23                                                                                  ##STR48##   H                                                                                ##STR49##  O O 241˜244° C. (i-PrOH)                                                         C.sub.18 H.sub.18 F.sub.3                                                     N.sub.3 O.sub.2.1/10H.sub.                                                    2 O C: 58.88 H: 5.00 N:                                                       11.50 C: 58.82 H: 4.88 N:                                                     11.45                          24*                                                                                ##STR50##   H                                                                                ##STR51##  O O 259˜261° C. (i-PrOH)                                                         C.sub.18 H.sub.18 F.sub.3                                                     N.sub.3 O.sub.2.HCl.H.sub.                                                    2 O C: 51.50 H: 5.04 N:                                                       10.01 C: 51.55 H: 4.79 N:                                                      9.92                         25                                                                                  ##STR52##   H                                                                                ##STR53##  O O Oil         m/e = 311 (M.sup.+), 178,                                                     60, 133, 91                   26                                                                                  ##STR54##   H                                                                                ##STR55##  O O 127˜128° C. (n-C.sub.6                                           H.sub.14 wash)                                                                            C.sub.17 H.sub.25 N.sub.3                                                     O.sub.2.1/5H.sub.2 O C:                                                       66.51 H: 8.34 N: 13.69 C:                                                     66.50 H: 8.34 N: 13.76        27                                                                                  ##STR56##   H                                                                                ##STR57##  O O 238˜241° C. (MeOH)                                                           C.sub.17 H.sub.18 N.sub.4                                                     O.sub.4  C: 59.64 H: 5.30                                                     N: 16.37 C: 59.44 H: 5.19                                                     N: 16.29                       28*                                                                                ##STR58##   H                                                                                ##STR59##  O O 267˜270° C. (H.sub.2                                                         C.sub.17 H.sub.18 N.sub.4                                                     O.sub.4.HCl.1/5H.sub.2 O                                                      C: 53.39 H: 5.11 N: 14.65                                                     : 53.33 H: 4.97 N: 14.71      29                                                                                  ##STR60##   H                                                                                ##STR61##  O S 194˜195° C. (EtOH)                                                           C.sub.17 H.sub.19 N.sub.3                                                     OS C: 65.15 H: 6.11 N:                                                        13.41 C: 65.24 H: 6.04 N:                                                     13.47                         30                                                                                  ##STR62##   H                                                                                ##STR63##  O O 217˜218° C. (AcOEt:EtOH)                                                     C.sub.19 H.sub.24 N.sub.4                                                     O.sub.2.1/5H.sub.2 O C:                                                       66.33 H: 7.15 N: 16.29 C:                                                     66.45 H: 7.22 N: 16.23        31                                                                                  ##STR64##   H                                                                                ##STR65##  O O 224˜225° C. (MeCN:EtOH)                                                      C.sub.18 H.sub.21 N.sub.3                                                     O.sub.2.1/10H.sub.2 O C:                                                      69.03 H: 6.76 N: 13.42 C:                                                     69.05 H: 6.80 N: 13.47        32                                                                                  ##STR66##   H                                                                                ##STR67##  O O 259˜260° C. (AcOEt:EtOH)                                                     C.sub.19 H.sub.21 N.sub.3                                                     O.sub.3.1/2H.sub.2 O C:                                                       65.50 H: 6.36 N: 12.06 C:                                                     65.78 H: 6.27 N: 11.93        33                                                                                  ##STR68##   H                                                                                ##STR69##  O O 218˜219° C. (AcOEt:EtOH)                                                     C.sub.18 H.sub.21 N.sub.3                                                     O.sub.3.1/5H.sub.2 O C:                                                       65.32 H: 6.52 N: 12.70 C:                                                     65.41 H: 6.43 N: 12.72        34                                                                                  ##STR70##   H                                                                                ##STR71##  O O 235˜238° C. (AcOEt                                                           C.sub.19 H.sub.22                                                             ClN.sub.3 O.sub.2.3/10H.su                                                    b.2 O C: 62.48 H: 6.24 N:                                                     11.50 C: 62.50 H: 6.09 N:                                                     11.38                         35                                                                                  ##STR72##   H                                                                                ##STR73##  O O 183˜184° C. (EtOH)                                                           C.sub.17 H.sub.17                                                             Cl.sub.2 N.sub.3 O.sub.2                                                      : 55.75 H: 4.68 N: 11.47                                                      C: 55.72 H: 4.56 N:                                                           11.37                         36                                                                                  ##STR74##   H                                                                                ##STR75##  O O 162˜163° C. (MeCN)                                                           C.sub.17 H.sub.17                                                             Cl.sub.2 N.sub.3 O.sub.2                                                      : 55.75 H: 4.68 N: 11.47                                                      C: 55.97 H: 4.54 N:                                                           11.68                         37                                                                                  ##STR76##   H                                                                                ##STR77##  O O 228˜229° C. (AcOEt                                                           C.sub.17 H.sub.18                                                             IN.sub.3 O.sub.2.7/10H.sub                                                    .2 O C: 46.85 H: 4.49 N:                                                      9.64 C: 46.55 H: 4.15 N:                                                      9.32                          38                                                                                  ##STR78##   H                                                                                ##STR79##  O O 208˜209° C. (AcOEt-MeCN-E                                        tOH)        C.sub.18 H.sub.18 N.sub.4                                                     O.sub.2.H.sub.2 O C:                                                          63.50 H: 5.93 N: 16.47 C:                                                     63.45 H: 6.14 N: 16.83        39                                                                                  ##STR80##   H                                                                                ##STR81##  O O 228˜229° C. (AcOEt                                                           C.sub.18 H.sub.21 N.sub.3                                                     O.sub.2 S.1/5H.sub.2 O C:                                                     62.30 H: 6.22 N: 12.11 C:                                                     62.33 H: 6.20 N: 11.86        40                                                                                  ##STR82##   H                                                                                ##STR83##  O O 183˜184° C. (MeCN:DMF)                                                       m/e = 330 (M.sup.+), 177,                                                     153                           41                                                                                  ##STR84##   H                                                                                ##STR85##  O O 124˜125° C. (n-C.sub. 6                                          H.sub.14 :AcOEt)                                                                          C.sub.22 H.sub.22 N.sub.2                                                     O.sub.2  C: 76.28 H: 6.40                                                     N: 8.09 C: 76.17 H: 6.40                                                      N: 8.06                       42                                                                                  ##STR86##   H                                                                                ##STR87##  O O 152˜153° C. (n-C.sub.6                                           H.sub.14 :AcOEt:EtOH)                                                                     C.sub.19 H.sub.18                                                             ClN.sub.3 O.sub.2 S C:                                                        58.83 H: 4.68 N: 10.83 C:                                                     58.99 H: 4.63 N: 10.80        43                                                                                  ##STR88##   H                                                                                ##STR89##  O O 203° C. (n-C.sub.6 H.sub.14                                            :EtOH)      C.sub.25 H.sub.26                                                             ClN.sub.3 O.sub.2  C:                                                         68.88 H: 6.01 N: 9.64 C:                                                      68.53 H: 5.89 N: 9.62         44                                                                                  ##STR90##   H                                                                                ##STR91##  O O 271˜273° C. (MeOH)                                                           C.sub.20 H.sub.20 N.sub.4                                                     O.sub. 4  C: 68.95 H:                                                         5.79 N: 16.08 C: 68.88 H:                                                     5.64 N: 16.09                 45                                                                                  ##STR92##   H                                                                                ##STR93##  O O 191˜192° C. (i-prOH)                                                         C.sub.19 H.sub.23 N.sub.3                                                     O.sub.2  C: 70.13 H: 7.12                                                     N: 12.91 C: 69.91 H: 7.15                                                     N: 13.01                      46                                                                                  ##STR94##   H                                                                                ##STR95##  O O 211˜212° C. (MeCN)                                                           C.sub.17 H.sub.17 F.sub.2                                                     N.sub.3 O.sub.2  C: 61.26                                                     H: 5.14 N: 12.61 C: 61.13                                                     H: 5.05 N: 12.78              47                                                                                  ##STR96##   H                                                                                ##STR97##  O O 195˜196° C. (MeCN)                                                           C.sub.17 H.sub.17 F.sub.2                                                     N.sub.3 O.sub.2  C: 61.26                                                     H: 5.14 N: 12.61 C: 61.06                                                     H: 5.01 N: 12.83              48                                                                                  ##STR98##   H                                                                                ##STR99##  O O 220˜221° C. (MeOH)                                                           C.sub.21 H.sub.27 N.sub.3                                                     O.sub.2  C: 71.36 H: 7.70                                                     N: 11.89 C: 71.26 H: 7.76                                                     N: 12.07                       ##STR100##                                                                   49                                                                                  ##STR101##  H                                                                                ##STR102## O O 183˜184° C. (MeCN)                                                           C.sub.17 H.sub.18                                                             ClN.sub.3 O.sub.2  C:                                                         61.54 H: 5.47 N: 12.66 C:                                                     61.38 H: 5.38 N: 12.62        50                                                                                  ##STR103##  H                                                                                ##STR104## O O 163˜165° C. (MeCN)                                                           C.sub.18 H.sub.21 N.sub.3                                                     O.sub.2  C: 69.43 H: 6.80                                                     N: 13.50 C: 69.53 H: 6.80                                                     N: 13.51                      51                                                                                  ##STR105##  H                                                                                ##STR106## O O 169˜196° C. (MeCN)                                                           C.sub.17 H.sub.18                                                             FN.sub.3 O.sub.2  C:                                                          64.75 H: 5.75 N: 13.33 C:                                                     64.59 H: 5.71 N: 13.34        52                                                                                  ##STR107##  H                                                                                ##STR108## O O 194˜196° C. (MeCN)                                                           C.sub.18 H.sub.18 F.sub.3                                                     N.sub.3 O.sub.2  C: 59.17                                                     H: 4.97 N: 11.50 C: 59.27                                                     H: 4.91 N: 11.58              53                                                                                  ##STR109##  H                                                                                ##STR110## O O 173˜175° C. (AcOEt:n-C.su                                        b.6 H.sub.14)                                                                             C.sub.19 H.sub.24 N.sub.3                                                     O.sub.3  C: 67.24 H: 6.24                                                     N: 12.38 C: 66.97 H: 6.24                                                     N: 12.26                      54                                                                                  ##STR111##  H                                                                                ##STR112## O O 134˜136° C.  (AcOEt:n-C.s                                        ub.6 H.sub.14)                                                                            C.sub.19 H.sub.24 N.sub.4                                                     O.sub.2  C: 67.04 H: 7.11                                                     N: 16.46 C: 66.92 H: 7.17                                                     N: 16.52                      55                                                                                  ##STR113##  H                                                                                ##STR114## O O Oil         C.sub.19 H.sub.23 N.sub.3                                                     O.sub.4.2/5H.sub.2 O C:                                                       62.59 H: 6.58 N: 11.52 C:                                                     62.43 H: 6.49 N: 11.64        56                                                                                  ##STR115##  H                                                                                ##STR116## O O 176˜178° C. (MeCN)                                                           C.sub.18 H.sub.21 N.sub.3                                                     O.sub.3  C: 66.04 H: 6.47                                                     N: 12.84 C: 66.86 H: 6.42                                                     N: 12.94                      __________________________________________________________________________     *Hydrochloride                                                           

Example 57 (R)-(+)-3-piperidyl 4-chlorophenycarbamate

(1) Two steps synthesis

(a) Into a solution of (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol(Reference Example 2) (23 g) in dry tetrahydrofuran (20 ml) were added4-chlorophenyl isocyanate (1.43 ml) and triethylamine (1.87 mi)successively at room temperature with stirring, and then the mixture wasstirred at room temperature for 10 hours. The reaction mixture wasdistilled under reduced pressure to give residues which was adsorbed onca. 20 g of silica gel with employment of 50 ml of methylene chlorideand purified through column chromatography (alumina, n-hexane:ethylacetate =5:1) to give (R)-(+)-N-tert-butoxycarbonyl-3-piperidyl4-chlorophenylcarbamate (3.07 g) of colorless prism crystal.

Melting point 160°-161° C.

Elementary analysis (%) for C₁₇ H₂₃ ClN₂ O₄ :

Calculated value C: 57.54, H: 6.53, N: 7.89.

Observed value C: 57.66, H: 6.55, N: 7.83.

[α]_(D) ²⁵ 46.76° (1=100, c 1.0, ethanol)

(b) Into a solution of the compound obtained (2.7 g) in (a) step intetrahydrofuran (50 mi) was added 2.4N-hydrochloric acid (20 mi) at roomtemperature with stirring and the mixture was refluxed with heating for5 hours. The reaction mixture was concentrated under reduced pressure,added with ca. 50 ml of hot water and insoluble matter was removed byfiltration to give filtrate. The filtrate was made to have PH value ofmore than 11 with gradual addition of potassium hydroxide under icecooling with stirring and extracted with ethyl acetate.

The organic layer was washed with saturated aqueous sodium chloridesolution to give a residue (1.18 g), which was then azeotropically twiceboiled with a little amount of acetonitrile added and was recrystallizedfrom acetonitrile to afford the title compound (1.43 g) of colorlessprism crystal.

Melting point 144°-145° C.

Elementary analysis (%) for C₁₂ H₁₅ ClN₂ O₂ :

Calculated value C: 56.59, H: 5.94, N: 11.00.

Observed value C: 56.57, H: 5.92, N: 11.10.

[α]_(D) ²⁵ 17.47° (1=100, c 1.0, ethanol)

(2) One step synthesis

Into a solution of (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol(Reference Example 2) (7.91 g) in dry tetrahydrofuran (60 ml) weresuccessively added 4-chlorophenyl isocyanate (5.03 ml) and triethylamine(6.57 ml) at room temperature with stirring, and thereafter the mixturewas stirred at room temperature for 10 hours. The reaction mixture wasdistilled off under reduced pressure to give residue, which was thendissolved into tetrahydrofuran (120 ml) added and was refluxed withheating for 7 hours after addition of 2.4N-hydrochloric acid (70 ml) atroom temperature. The reaction mixture was concentrated under reducedpressure, added with ca. 100 ml of hot water and the resulted insolublematter was removed by filtration to give filtrate. To this filtrate wasslowly added with potassium hydroxide under ice cooling with stirring tohave pH value of more than 11, and was stirred, as it was, under icecooling for 1 hour and further at room temperature for 1 hour. Theprecipitated crystal was collected through filtration and this crystalwas recrystallized from acetonitrile to give the title compound (7.3 g)as colorless prism crystal, the spectrum data of which accorded withthose obtained in (1).

Example 58 (R)-(-)-[3-(1-(4-pyridyl)piperidyl)] 4-chlorophenylcarbamate

Into a solution of (R)-(+)-3-piperidyl 4-chlorophenylcarbamate (Example57) (9.3 g) in isoamyl alcohol (170 ml) were successively added4-chloropyridine hydrochloride(6.02 g), sodium hydrogen carbonate (4.6g) and sodium acetate (3.59 g) at room temperature, and after stirred asit was at room temperature for 30 minutes, the mixture was added withsodium iodide (6.02 g) and refluxed with stirring for 4 hours. Thereaction mixture was subjected to celite filtration to remove inorganicmatter and this inorganic matter was washed with ethyl acetate, whichwas then combined with the former filtrate. The filtrate was washed withsaturated sodium hydrogen carbonate and the organic layer was separated,while the aqueous layer was again extracted with ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate, thesolvent thereof was distilled off under reduced pressure and theobtained residue was azeotropically boiled with toluene to give asemi-solid matter. This was purified through column chromatography(alumina, methylene chloride) and fractions including the aimed compoundwere collected to give oily matter by distillation off of the solvent,which was then dissolved with addition of acetonitrile and crystallizedby distillation of the solvent. This crude crystal was recrystallizedfrom acetonitrile to give the title compound (5.49 g) as colorless prismcrystal.

Melting point 144°-145° C.

Elementary analysis (%) for C₁₇ H₁₈ ClN₃ O₂ :

Calculated value C: 61.54, H: 5.47, N: 12.66.

Observed value C: 61.45, H: 5.38, N: 12.66.

[α]_(D) ²⁵ -29.11° (1=50, c 1.1, ethyl acetate) Example 59(S)-(-)-3-piperidyl 4-chlorophenylcarbamate

(1) Two steps synthesis

Likewise as in Example 57(1)-a, from(S)-(+)-N-tert-butoxycarbonyl-3-piperidinol (Reference Example 4) wasobtained (S)-(-)-N-tert-butoxycarbonyl-3-piperidyl4-chlorophenylcarbamate (2.58 g) as colorless prism crystal.

Melting point 161°-162° C.

Elementary analysis for C₁₇ H₂₃ ClN₂ O₄ :

Calculated value C: 57.54, H: 6.53, N: 7.89.

Observed value C: 57.73, H: 6.57, N: 7.90.

[α]_(D) ²⁵ - 46.56° (1=100, c=1.0, ethanol)

Further, likewise as in Example 57(1)-b, from the obtained compound (2.3g) was obtained the title compound (1.07 g) as colorless prism crystal.

Melting point 143°-144° C.

Elementary analysis for C₁₂ H₁₅ ClN₂ O₂ :

Calculated value C: 56.59, H: 5.94, N: 11.00.

Observed value C: 56.60, H: 5.91, N: 11.11.

[α]_(D) ²⁵ - 17.21° (1=100, c 1.0, ethanol)

(2) One step synthesis

Likewise as in Example 57(2), from(S)-(+)-N-tert-butoxycarbonyl-3-piperidinol (Reference Example 4) (9.3g) was obtained the title compound (9.48 g) as colorless prism crystal.

The spectrum data thereof accorded with those obtained in (1).

Example 60 (S)-(+)-[3-(1-(4-pyridyl)piperidyl)] 4-chlorophenylcarbamate

With employment of (S)-(-)-3-piperidyl 4-chlorophenylcarbamate (Example59) (9.5 g), 4-chloropyridine hydrochloride (6.2 g), sodium hydrogencarbonate (4.7 g), sodium acetate (3.67 g), sodium iodide (6.15 g) andisoamyl alcohol (150 ml), likewise as in Example 58, was obtained thetitle compound (6.81 g) as colorless prism crystal.

Melting point 143°-144° C.

Elementary analysis (%) for C₁₇ H₁₈ ClN₃ O₂ :

Calculated value C: 61.54, H: 5.47, N: 12.66.

Observed value C: 61.60, H: 5.41, N: 12.69.

[α]_(D) ²⁵ 28.48° (1=50, c 1.02, ethyl acetate) Reference Example 1(R)-(+)-3-piperidinol (L)-(+)-4-chlorophenyl tartaric acid amide salt

According to the method described in J. Med. Chem., 15, 1085 (1972) andEur. J. Med. Chem., 11, 461 (1976), from (±)-3-piperidinol was obtainedthe title compound as colorless heedle crystal.

Melting point 153°-155° C.

Elementary analysis for C₁₅ H₂₀ ClN₂ O₆ ·H₂ O:

Calculated value C: 47.56, H: 6.12, N: 7.40.

Observed value C: 47.77, H: 6.12, N: 7.49.

[α]_(D) ²⁵ 78.07° (1=100, c 0.75, distilled water) Reference Example 2(R)-(-)-N-tert-butoxycarbonyl-3-piperidinol

Into a suspension of the compound (37.88 g) synthesized in the ReferenceExample (1) in a mixture (300 ml) of methylene chloride:methanol (1:1)were successively added diiso-propylethylamine (38.41 ml) and a solutionof di-tertbutyl dicarbonate (22.91 g) in methylene chloride (50 ml) atroom temperature with stirring.

After stirred at room temperature for 3 hours, the mixture was distilledoff under reduced pressure to give residue, which was then dissolvedinto methylene chloride (300 ml). This organic layer was washed twicewith saturated aqueous solution of sodium hydrogen carbonate and oncewith saturated aqueous solution of sodium chloride to give residue. Thiswas purified through column chromatography (silica gel, n-hexane:ethylacetate=1:2) and further the solvent was distilled under reducedpressure (200° C./0.7 mm Hg) to give the title compound (21.03 g) ascolorless oily product.

Elementary analysis for C₁₀ H₁₉ NO₃ :

Calculated value C: 59.68, H: 9.52, N: 6.96.

Observed value C: 59.50, H: 9.72, N: 6.99.

[α]_(D) ²⁵ - 22.89° (1=50, c 1.7, ethanol) Reference Example 3(S)-(-)-3-piperidinol (D)-(-)-4-chlorophenyl tartaric acid amide salt

According to the method described in J. Med. Chem., 15, 1085 (1972) andEur. J. Med. Chem., 11, 461 (1976), from (±)-3-piperidinol wassynthesized the title compound as colorless needle crystal.

Melting point 153°-154° C.

Elementary analysis for C₁₅ H₂₀ ClN₂ O₆ ·H₂ O:

Calculated value C: 47.56, H: 6.12, N: 7.40.

Observed value C: 47.31, H: 6.12, N: 7.36.

[α]_(D) ²⁵ - 78.37° (1=50, c 0.76, distilled water) Reference Example 4(S)-(+)-N-tert-butoxycarbonyl-3-piperidinol

Except replacement of base, di-iso-propylethylamine in Reference Example2 with triethylamine, with employment of the same procedure, from theoptically active salt (17.7 g) synthesized in Reference Example 3 wasobtained the title compound (9.36 as colorless oily product.

Elementary analysis for C₁₀ H₁₉ NO₃.

Calculated value C: 59.68, H: 9.52, N: 6.96.

Observed value C: 59.49, H: 9.70, N: 6.98.

[α]_(D) ²⁵ 23.48° (1=50, c 1.6, ethanol) Experiment Action againstamnesia induced by exposure to carbon dioxide gas

The experimental animals employed were the Std: ddy strain male mice(Japanese SLC) having body weight of 23-32 g (five weeks old). Theapparatus used was a passive avoidance apparatus of a step-through type(made by O'Hara Co., Ltd.). In the aquisition trial, each mouse wasplaced in the light compartment, a guillotine door of partition thereofwas opened after 10 seconds, the guillotine door was closed as soon asthe mouse moved into the dark compartment and an electric shock of 33-50v was given for 1 second through the metal grid bars of the floor.Immediately after the electric shock was given, the mouse was taken outand was accommodated in a container having volume of ca. 300 ml filledwith carbon dioxide gas. After immediately exposed to carbon dioxide gashaving flow rate of ca. 5 liter/min. for 25-45 seconds, the mouse wastaken out and was reanimated by artificial breathing. The retentiontrial was carried out after 24 hours. In the retention trial, the mousewas again placed in the light compartment, the time till the movement tothe dark compartment was measured as a reaction latency until maximum300 seconds and the mouse showing latency beyond it was deemed as 300seconds. In addition, immediately after aquisition trial, a group not toexposed to carbon dioxide gas (comparison group of non-amnesia) was alsomade. The mouse was grouped per 10-30, the subject medicament was orallyadministered immediately after exposed to carbon dioxide gas and onehour before the retention trial. The amelioration rate was calculatedaccording to the following equation and the result was shown in Table 1.##EQU1##

Effect on amnesia induced by carbon dioxide

    ______________________________________                                        Effect on amnesia induced by carbon dioxide                                               Dose   Number   Reaction  Rate of                                             (mg/   of       latency (sec)                                                                           improve-                                Compound    kg)    animal   Means ± S.E.                                                                         ment (%)                                ______________________________________                                        Non-treated --     20       278.5 ± 12.0                                                                         42.9                                    CO.sub.2 treated mouse                                                                    --     20        54.8 ± 15.2                                   Example 2   10     20       150.7 ± 27.1**                                 Non-treated --     30       269.7 ± 12.1                                                                         76.8                                    CO.sub.2 treated mouse                                                                    --     30       103.6 ± 18.5                                   Example 2   30     30       231.2 ± 19.0**                                 Non-treated --     20       300.0 ± 0                                                                            45.3                                    CO.sub.2 treated mouse                                                                    --     20        87.3 ± 18.9                                   Example 49  10     20       154.0 ± 27.2                                               30     20       183.7 ± 26.3**                                 Non-treated --     10       300.0 ± 26.3**                                                                       -59.8                                   CO.sub.2 treated mouse                                                                    --     10       170.4 ± 26.3**                                 Nicardipine  5     10        92.9 ± 26.3**28.1                             Non-treated --     19       282.5 ± 12.1                                                                         37.9                                    CO.sub.2 treated mouse                                                                    --     20       131.1 ± 23.9                                   Bifemelane  100    19       188.5 ± 27.1                                   Non-treated --     30       300.0 ± 0                                                                            30.1                                    CO.sub.2 treated mouse                                                                    --     30       184.5 ± 18.3                                   Indeloxazine                                                                              40     30       219.3 ± 17.8                                   Non-treated --     10       300.0 ± 0                                                                            15.2                                    CO.sub.2 treated mouse                                                                    --     10       152.9 ± 37.8                                   Compound A  100    10       175.3 ± 36.7                                   ______________________________________                                         *: P < 0.05, **: P < 0.01 There is a significant difference to CO.sub.2       treated group                                                                 Compound A: 3(1-methylpiperidinyl) phenylcarbamate (Egypt. J. Pharm. Sci.     26. 267(1985))                                                           

As mentioned above, the carbamic acid derivatives of the presentinvention show excellent improving activity to disturbance of memorywhile the improving activity to disturbance of memory of theconventional treatment medicament to cerebrovascular disturbance(Nicardipine)and the conventional activating medicament to cerebralmetabolism (Bifemelane, Indeloxazine) is vitiated or not enough.Accordingly, the compounds of the present invention are effective asanti-dementia medicament.

What is claimed is:
 1. A carbamic acid represented by formula (I)##STR117## wherein R¹ denotes hydrogen atom or lower alkyl group, R²denotes lower alkyl group which may be substituted with halogen atom,phenyl group which may have at least one substituent, naphthyl group, orfive- or six-membered heterocyclic ring or its benzene-condensed ring,and X and Y, being same or different, denote sulfur atom or oxygen atomor their acid addition salts.
 2. An anti-dementia composition comprisingan effective amount of at least one of the carbamic acids represented byformula (I) ##STR118## wherein R¹ denotes hydrogen atom or lower alkylgroup, R² denotes lower alkyl group which may be substituted withhalogen atom, phenyl group which may have at least one substituent,naphthyl group, or five- or six-membered heterocyclic ring or itsbenzene-condensed ring, and X and Y, being same or different, denotesulfur atom or oxygen atom or their acid addition salts, in combinationwith a pharmaceutically suitable carrier.